Filaggrin is a major differentiation product of terminally differentiating mammalian epidermal cells, that is thought to be involved in the aggregation and specific alignment of keratin intermediate filaments during the final stages of differentiation. Thus filaggrin is an important example of an intermediate filament-associated protein. We have isolated both cDNA and genomic clones which show that filaggrin is initially expressed as a large polyprotein precursor, filaggrin, that is subsequently proteolytically processed into individual functional filaggrin molecules. In the human system, the precursor consists of 3 allelic size variants, containing 10, 11 or 12 tandem repeats that segregated by normal Mendelian genetic mechanisms. In addition, these repeats show considerable sequence variation, so that any two repeats are only about 85% homologous to each other; so far, we find that of the 324 amino acid residues of the filaggrin repeats, about 40% of the positions are variable. We have constructed genomic fragments for the production of transgenic mice. We have begun a systematic analysis of regulatory sequences that control the expression of this gene system. We are studying the method of interaction of filaggrin with keratin intermediate filaments by use of solid state NMR techniques. Since there are a number of keratinizing disorders of the skin for which there is some evidence involving incorrect expression of the profilaggrin gene, we have begun a systematic search for the possible role of filaggrin in genetic diseases of keratinization.